3-amino-2,4,6-triiodobenzoic acid derivatives



United States Patent 3,484,481 3-AMlN0-2,4,6-TRIIODOBENZOIC ACIDDERIVATIVES Werner Obendorf-and Irmgard Lindner, Linz (Danube), Austria,assignors to Osterreichische Sticlrstolfwerke Aktiengesellschaft, Linz(Danube), Austria No Drawing. Filed Mar. 28, 1966, Ser. No. 537,714Claims priority, application Austria, Apr. 9, 1965, A 3,278/65, A3,279/65 Int. Cl. C07c 103/ 84, 103/28; A6lk 27/08 US. Cl. 260518 11Claims ABSTRACT OF THE DISCLOSURE Derivatives of3-amino-2,4,6-triiodobenzoic acid having utility as X-ray contrastagents which are of the formula in which Ac is an acyl residue of analkanoic acid having up to four carbon atoms, R is selected from thegroup consisting of lower alkyl and alkenyl having 3 or 4 carbon atoms,R is selected from the group consisting of hydrogen, alkyl and isoalkylhaving up to four carbon atoms, alkenyl having 3 or 4 carbon atoms,w-alkoxyalkyl having 3 or 4 carbon atoms, benzyl and a-furanomethyl, Xis selected from the group consisting of methylene, ethylene,a-methylethylene and fl-methylethylene and Y is selected from the groupconsisting of hydrogen, methyl, ethyl and a residue of a non-toxicinorganic or organic base.

The present invention relates to derivatives of 3-amino-2,4,6-triiodobenzoic acid, which are valuable X-ray contrast agents, andwhich are particularly suitable for oral cholecystography. The inventionalso relates to an advantageous process for the preparation of3-amino-2,4,6- triiodobenzoic acid derivatives.

In accordance with the invention there is provided a3-amino-2,4,6-triiodobenzoic acid derivative having the formulaCO-N-X-COOY RJ-N-Ao I in which Ac is an acyl residue of an aliphaticmono carboxylic acid having up to'4 carbon atoms, R is a lower alkylgroup or an alkenyl group having 3 or 4 carbon atoms, R is a hydrogenatom, an alkyl or isoalkyl group having up to 4 carbon atoms, analkenyl'group having 3 or 4 carbon atoms, an w-alkoxy-alkyl group having3 or 4 carbon atoms, or a benzyl or u-furanomethyl group, X is amethylene, ethylene, a-methylethylene or fi-methylethylene group and Yis a hydrogen atom, a methyl or ethyl group or a residue of a non-toxicinorganic or organic base.

Examples of preferred compounds of the invention are fl-aminopropionicacid and fi-amino-a-methyhpropionic acid derivatives of Formula I, inwhich Ac is an acetyl or propionyl group, R is a methyl, ethyl or allylgroup and R? is a methyl, ethyl, propyl, allyl or 'ymethoxypropylradical.

ICC

Compounds of Formula I are suitable above all for Showing up the ballbladder system in radiographic examination. They are particularlydistinguished by being rapidly and completely resorbed from the gut andrapidly excreted through the gall bladder, thus leaving very highconcentrations of iodine in the gall bladder. Thus, for example, withthe compound N-(3-N-acetyl-N-methylamino-2,4,6-triiodobenzoyl) NallyLfi-amino-a-methy1 propionic acid sodium salt, in tests carried outwith cats, visible pictures of the gall bladder could be obtained withinone to two hours after oral administration and optimum quality pictureswere obtainable 3 hours after administration. The gall bladder islikewise shown up quickly, for example, by administering the followingcompounds:

N (3-N-acetyl-N'-methylamino-2,4,6-triiodobenzoyl)-N-allyl-B-aminopropionic acid sodium salt,

N-(3-N-propionyl-N-ethylamino 2,4,6 triiodobenzoyI-N-M-methoxy-propyl ,8aminopropionic acid sodium salt,

N-(3-N-acetyl-N-allylamino 2,4,6 triiodobenzoyl)-N-methyl-fl-amino-propionic acid sodium salt, and

N-(3-N-acetyl-N-allyl-amino 2,4,6 triiodobenzoyl)-N-ethyl-B-aminopropionic acid sodium salt.

The compounds surprisingly possess a low toxicity favourable for oralgall bladder contrast agents. The acute LD i.v. (for white mice) of thecompound N-(3- Nacetyl-N'-methylamino-2,4,6-triiodcbenzoyl)-N-allylfl-amino-a-methylpropionicacid is 0.93 (0.82-1.07); that of the compoundN-(3-N-acetyl-N-allylamino-2,4,6-triiodobenzoyl)-N-methyl-[3-amino-propionicacid is in fact only 1.66 (1.50-1.83).

The compounds of Formula I are thus suitable for use in rapidcholecystography following oral administration. Accordingly, theinvention also provides an X-ray contrast agent comprising, as theactive ingredient a compound having the Formula I herein in admixturewith an inert solid or liquid filler or diluent. The compounds arepreferably used in the form of their salts, for example the sodium,methylglucamine and diethanolamine salts, which may be administered inthe form of pills or capsules.

The compounds of Formula I are related, from the structural point ofview, to the compounds disclosed in United States Patent No. 3,051,745to Obendorf and in the copending application Ser. No. 170,823, nowPatent No. 3,334,134 to Obendorf et al. and represent an improvement inthese older, related compounds. They differ from the compounds disclosedin U.S.P. 3,051,745, in that two substituents are present in the aminogroup situated in the 3-position of the phenyl ring. As regards thecompounds of the copending application Ser. No. 170,823, they differfrom the latter in that they have not only an acyl group but also analkyl or alkenyl group on the amino group in the 3-position. Theintroduction of the alkyl and alkenyl groups greatly alters theproperties of the compounds. Whilst the compounds according to Ser. No.170,823 are not resorbed or are only resorbed to a limited extent in thegut, although they give good pictures of the gall bladder afterintravenous administration and possess very low toxicities, thecompounds of the present invention are distinguished in effect by beingrapidly resorbed from the gut and rapidly excreted, after oraladministration. The compounds according to U.S.P. 3,051,-

' 745, although likewise-oral gall bladder X-ray contrast agents, aretaken up and excreted more slowly, so that optimum pictures can beobtained only more than 12 hours after administration and generally 14hours following administration, which is usually the case with oral gallbladder X-ray contrast agents. 1

The present invention further provides a process for preparing acompound having the Formula I which comprises reacting an acid chloridehaving the formula:

in which R and Ac are defined above, at an elevated temperature, with anamino acid ester having the formula:

in which R is a lower alkyl group and R and X are as defined above, and,if desired, thereafter saponifying the ester group. From thesaponification solution compounds of Formula I can be obtained directlyas acids or salts.

The reaction is preferably carried out in an inert organic solvent, forexample, chloroform, acetone, dioxane, tetrahydrofuran, methylethylketone, chlorobenzene or toluene. It is however also possible to carryout the operation without using a solvent. The separation of thecompounds of Formula I can be effected by evaporating the solution,which has been purified by various washing procedures, and the estervapourisation residue is generally saponified directly. If the organicsolvent used for the reaction is miscible with water, it must beevaporated after the reaction is completed and replaced by awaterimmiscible solvent, prior to commencing the washing process. Thesaponification process is preferably an alkaline saponification process,for example, aqueous or acoholic sodium or potassium hydroxide solutionmay be employed, and generally heating is carried out for a shortperiod. The alkali metal salts can either be obtained directly from thealkaline saponification solution, eg by precipitation with an organicsolvent, or the solution is acidified and compounds of Formula I areseparated out in the form of the free acid. The acids and the salts canbe converted into one another.

The new acid chloride of Formula II which is used as a starting materialin the above process can be obtained either by alkylation of3-acylamino-2,4,6-triiodobenzoyl chloride With an alkylating agent, suchas an alkyl halide or a dialkyl sulphate, or by reacting N-alkyl-N-acyl-2,4,6-triiodobenzoic acid with thionyl chloride, preferably in an inertorganic medium.

The compounds of Formula I exist in part in two geometrically isomericforms which can be separated from one another in principle.

The process of the invention is illustrated in the following examples.

EXAMPLE 1 18.45 g. of 3 N-allyl-N-acetyl-2,4,6 triiodobenzoyl chlorideare dissolved in 30 ml. of chloroform and treated with 8 g. of B-aminopropionic acid ethyl ester. When the reaction has subsided the mixtureis boiled for another hour under reflux; it is then cooled and thesolution diluted with chloroform. After washing the latter with dilutehydrochloric acid, water, sodium bicarbonate solution and more water,the chloroform solution is dried and evaporated. The vaporisationresidue is dissolved in alcohol, and after adding 50 ml. 1 N causticsoda is again heated to boiling for 10 minutes. The alkaline solutionthus obtained is then diluted with water, filtered over charcoal andacidified with hydrochloric acid to a pH of 1, whereby the crude acidprecipitates out and is recrystallised from ethyl acetate. There isobtained 13.5 g. of N-(3-N'-acetyl-N'-allyl amino-2,4,6 triiodobenzoyl)-fi aminopropionic acid having a M. Pt. of 187 to 193 C., correspondingto a yield of 67.5% of theory. This acid can be converted into thesodium salt by treating with the e uivalent amoun of q eous odi m hydroxde 4 EXAMPLE 2 23.56 g. of 3-N-methyl-N-acetyl-2,4,6 triiodobenzoylchloride are dissolved in 60 ml. pure chloroform and are treated with15.3 g. of N-a-furanomethyl-/8-aminopropionic acid methyl ester(obtained by reacting ozfuranomethyl-amine with methyl acrylate). Afterthe reaction has subsided the mixture is boiled for a further 2 hoursunder reflux. The solution is then diluted With about 200 ml. chloroformand thereafter washed with dilute hydrochloric acid, water, sodiumbicarbonate solution and more water. After drying the chloroform isevaporated off and the vapourisation residue is saponified by heatingwith an excess of caustic soda solution in methanol. The crude acidprecipitates out on acidification and is recrystallised from ethylacetate. There are obtained 24.1 g. ofN-(3-N-acetyl-N'-methylamino-2,4,6- triiodobenzoyl)-N-a'-furanomethyl [3aminopropionic acid having a M. Pt. of to 156 C., corresponding to ayield of 86% of theory.

The acid chloride used as starting material is obtained as follows:

57.5 g. of N-acetylamino-2,4,6-triiodobenzoyl chloride are dissolved in500 ml. of dioxane, 26 g. of dimethyl sulphate are added and this isfollowed by dropwise adition of 100 ml. 4 N caustic soda at 5 C. duringa period of 30 minutes. The resulting emulsion was stirred for 30minutes at room temperature and subsequently 800 ml. of ether werepoured on top of the solution, this resulting in the formation of twolayers. The lighter layer was extracted with sodium bicarbonate solutionand dried with sodium sulphate. On concentrating the solution thus dried3-N-methyl-N-acetylamino 2,4,6 triiodobenzoyl chloride crystallises out,M. Pt. 183 to 190 C. After recrystallisation from acetone it has a M.Pt. of 186 to 192 C.

The following acid chlorides may be obtained in a similar manner:

3-N-acetyl-N-allylamino-2,4,6-triiodobenzoyl chloride, M.

pt. 124 to 126 C.

3-N-acetyl-N-methylamino-2,4,6 triiodobenzoyl chloride,

M. Pt. 186 to 190 C.

3-N-propionyl-N-methylamino-2,4,6-triiodobenzoyl chloride, M. Pt. 158 to166 C.

The following compounds may be prepared in a similar manner to thatdescribed in Examples 1 and 2.

N- 3 -N'-acetyl-N'-methylamino-2,4,6-triiodobenzoylN-3-methoxypropyl-fl-aminobutyric acid, M. PL, to 175 C.,

N-(3-N'-acetyl-N-ethylamino-2,4,6-triiodobenzoyl)-N-n-propyl-fl-amino-a-methylpropionic acid, M. Pt. to 178 C., I

N- 3-N-acetyl-N'-methylamino-2,4,6-triiodobenzoyl)N-n-propyl-fl-amino-a-methylpropionic acid M. Pt. 178 to 186 C.,

N-(3-N-acetyl-N-methy1arnino-2,4,6-triiodobenzoyl)-N-isopropyl-fi-amino-a-methylpropionic acid, M. Pt.

N (3 -N-acetyl-N-ethylamino-2,4,6-triiodoben zoyl N-allylamino aceticacid, M. Pt. 190 to 198 C.,

N-( 3 -N-acetyl-N-ethylamino-2,4,6-triiodobenzoylN-methyl-fi-aminopropionic acid, M. Pt. amorph.,

N- 3-N-acetyl-N'-ethylamino-2,4,6-triiodobenzoylN-n-propyl-fi-aminopropionic acid, M. Pt. 186 to 194 CN-(3-N-acetyl-N-ethylamino-2,4,6-triiodobenzoyl)-N-isopropyl-,8-amino-a-methylpropionic acid,

M. Pt. 166 to 172 C.,

N- 3-N-acetyl-N-ethylamino-2,4,6-triiodobenzoyl)N-allyl-fl-amino-a-mcthylpropionic acid, M.

Pt. 182 to 191 C.,

N-(3-N'-propionyl-N'-methylamino-2,4,6-triiodobenzoyl)-N-3-methoxypropyl-[i-aminopropionic, acid, M. pt. 137 to 142 C.,

N-(3-N-propionyl-N'-methylamino-2,4,6-triiodobenzoyl-N-3-methoxypr0pyl-p-aminopropionic acid, M. Pt. 150 to 154 C.,

N-(3-N'-propi0nyl-N-ethylamino-2,4,6-triiodobenzoyl)-N-3-methoxypropyl-/3-aminopropionic acid, M. Pt. 158 to 162 C.,

N-(3-N-propionyl-N-n-propylamino-2,4,6-triiodobenzoyl)-N-3-methoxypropyl-p-arninopropionicacid, M. Pt. 148 to 151 C.,

N-(3-N'-acetyl-N-al1ylamino-2,4,6-triiodohenzoyl) -N- allylamino aceticacid, M. Pt. 190 to 195 C.,

N-(3-N'-acety1-N'-a1lylamino-2,4,6-triiodobenzoyl)-N-allyl-fi-aminopropionic acid, M. Pt. 147 to 152 C.,

N-(3-N'-acety1-N-allylamino-2,4,6-triiodobenzoyl)- aminoacetic acid, M.Pt. 185 to 189 C.,

N- 3-N'-acetyl-N'-methy1amino-2,4,6-triiod0benzoyl) p-aminopropionicacid, M. Pt. 132 to 158 C.,

N- 3-N'-acetyl-N-ethylamino-2,4,6-triiodobenzoyl p-aminopropionic acid,M. Pt. 126 to 137 C.,

N-(3-N-acetyl-N-n-propylamino-2,4,6-triid0benzoyl) B-aminopropionicacid, M. Pt. 125 to 134 C.,

N- 3-N'-acetylN-ethylamino-2,4,6-triiodobenzoyl -N-allyl-B-aminopropionic acid, M. Pt. 179 to 183 C.,

N-(3-N-acety1-N'-allylamino-2,4,6-triiodobenzoy1)-N-methyl-,B-aminopropionic acid, M. Pt. 115 C.,

N-( 3-N-acetyl-N-al1ylamino2,4,6-triiodobenzoyl)-N-ethyl-,B-aminopropionic acid, M. Pt. 92 to 102 C.,

N- 3-N-acetyl-N'-allylamino-2,4,6-triiodobenzoyl -N-n-propyl-/3-aminopropionic acid, M. Pt. 169 to 171 C.

N-(3-N-acetyl-N-al1ylamino-2,4,6-triiodobenzoy1)-N-3-methoxypropyl-fi-aminopropionic acid, M. Pt. 63 to 67 C.,

N- 3-N-acetyl-N'-allylamino-2,4,6-triiodobenzoyl -N-a-furanomethyl-fl-aminopropionic acid, M. Pt. 155 to 159 C.,

N-(3-N-acetyl-N'-methylaminc-2,4,6-triiodobenzoyl)-15-amino-a-methylp'ropionic acid, M. Pt. 138 to 146 C.,

N-(3-N-acety1-N'-ethylamino--2,4,6-triiodobenzoy1\)#3-amino-a-methylpropionic acid, M. Pt. 174 to 178 C.,

N- 3-N'-acetyl-N'-allylamino-2 ,4,6-triidobenzoyl)8-amino-wmethylpropionic acid, M. Pt. 195 to 200 C.,

N-(3-N'-acetyl-N'-methylamino-2,4,6-triiodobenzoyl)-N-benzyl-{3-amino-a-methylpropionicacid, M. Pt. 120 to 125 C.,

N-(3-N-propiony1-N'-methylamino-2,4,6-triiodobenzoyl)-;8-aminopropionicacid, M. Pt. 120 to 130 C.

6 N-(3-N'-propionyl-N'-ethylamino-2,4,6-triiodobenzoyl)-/8-aminopropionic acid, M. Pt. to C. N-3-N-propionyl-N-methylamino-2,4,6-triiodobenzoyl)-N-ethyl-fi-aminopropionicacid, M. Pt. to 173 C.,N-(3-N'-propionyl-N-ethylamino-2,4,6-trii0dobenzoyl)-N-ethyl-;8-amin0propionicacid, M. Pt. 174 to 179 C.N-(3-N-propionyl-N-methylamin0-2,4,6-triiodobenzoyl)-N-n-propyl-B-aminopropionicacid, M. Pt. 187 to 193 C.N-(3-N-propionyl-N-ethylamino-2,4,6--triiodobenzoyl)-N-n-propyl-;9-aminopropionicacid, M. Pt. to 175 C. and 210 to 215 C.,

JN-(3-N-propi0nyl-N'-allylamino-2,4,6--triiodobenzoyl)-N-3-methoxypropyl-8-aminopropionic acid, M. Pt. 67 to 75 C., isomeric form M. Pt. 63 to 74C.,

N-(3-N'-propiony1-N'-methylamino-2,4,6-triiodobenzoyl)-N-allyl-B-aminopropionic acid,

M. Pt. 182 to 185 C.,

N-(3-N'-propiony1-N-ethylamino-2,4,6-triiodobenzoyl-N-allyl-/8-aminopropionic acid,

M. Pt. 149 to 156 C.,

N-(3-N'-propionyl-N'-a1lylamino-2,4,6-triiodobenzoyl)-N-allyl-B-aminopropionic acid, M. Pt. 94 to 99 C.,

N-(3-N-propionyl-N-methylamino-2,4,6-triiodobenzoyl)-N-u-furanomethyl-B-aminopropionicacid, M. Pt. 158 to 161 C.,

N-(3-N-propionyl-N-ethylamino-2,4,6-triiodobenzoyl)-N-a-furanomethyl-p-aminopropionic acid, M. Pt. 149 to 151 C.,

N-(3-N'-propionyl-N'-allylamino-2,4,6-triiodobenzoyl)-N-a-furanomethyl-fl-aminopropionicacid, M. Pt. 86 to 92 C.,

N-(3-N'-propi0nyl-N-methylamino-2,4,6-triiodobenzoyl)-/3-amino-a-methylpropionicacid, M. Pt. 213 to 215 C.,

N- (3-N-popionyl-N-ethylamino-2,4,6-triiodobenzoyl)-,6-amino-a-methylpropionicacid, M. Pt. 207 to 210 C.,

N-(3-N-propionyl-N'-allylamino-2,4,6-triiodobenzoyl)-/3-amino-a-methylpropionicacid, M. Pt. 230 to 232 C.,

N-(3-N'-propiony1-N-methylamino-2,4,6-triiodobenzoyl)-N-allyl-/8-amino-a-methylpropionicacid, M. Pt.160 to 165 C., and

N-(3-N'-propi0ny1-N'-ethylamino-2,4,6-trii0dohenzoyl)-N-allyl-fl-amino-ot-methylpropionicacid,

M. Pt. 154 to 160 C.,

and the sodium salts thereo1.

The following examples illustrate the preparation of X-ray contrastagents according to the invention.

EXAMPLE 3 750.0 g. of N-(3-N'-methylaminc-2,4,6-triiodobenzoyl)-N-n-propyl-fl-amino-a-methylpropionic acid sodium salt are admixed with157.0 g. of starch, 26.4 g. of talc and 6.6 g. of magnesium stearate.The mixture is homogenised and 940 mg. tablets are extruded from themixture. Each of the tablets contains 750 mg. of active compound.

EXAMPLE 4 EXAMPLE 5 1000.0 g. ofN-(3N'-acetyl-N'-ethylamino-2,4,6-triidobenzoyl)-N-isopropyl-}8-amino-a-methylpropionicacid are made into a paste with 400 m1. starch paste and 20 g.

maize starch. This is granulated in a cosventional manner and dried invacuo. The finished granulate is admixed with further amounts of 100 g.of maize starch and g. of magnesium stearate and extruded into tabletshaving an active compound content of 500 mg.

EXAMPLE 6 500 mg. ofN-(3-N-acetyl-N-allylamino-2,4,6-triiodobenzoyl)-N-(methyl-B-aminopropionicacid sodium salt is admixed with 300 mg. of arachis oil and 50 mg. oflecithin to form a fluid paste which is placed into gelatin capsules.These are suitable for oral administration.

Pastes for capsules or tablets can also be made in a similar manner fromany of the other compounds prepared according to Examples 1 and 2.

We claim:

1. A 3-amino-2,4,6-triiodobenzoic acid derivative having the formula:

in which Ac is an acyl residue of an alkanoic acid having up to fourcarbon atoms, R is selected from the group consisting of lower alkyl andalkenyl having 3 or 4 carbon atoms, R is selected from the groupconsisting of hydrogen, alkyl and isoalkyl having up to four carbonatoms, alkenyl having 3 or 4 carbon atoms, w-alkoxyalkyl having 3 or 4carbon atoms, benzyl and a-furanomethyl, X is selected from the groupconsisting of methylene, ethylene, ot-methylethylene andfi-methylethylene and Y is selected from the group consisting ofhydrogen, methyl, ethyl and a residue of a non-toxic inorganic ororganic base.

2. A 3-amino-2,4,6-triiodobenzoic acid derivative according to claim 1having the formula:

3. A 3-amino-2,4,6-triiodobenzoic acid derivative acr cording to claim 1having the formula in which R is selected from the group consisting ofmethyl, ethyl and allyl, R is selected from the group consisting ofmethyl, ethyl, n-propyl, allyl and 'y-methoxypropyl and Y is selectedfrom the group consisting of hydrogen, methyl, ethyl and a residue of anon-toxic inorganic or organic base.

4. A 3-amino-2,4,6-triiodobenzoic acid derivative according to claim 1having the formula in which R is selected from the group consisting ofmethyl, ethyl and allyl, R is selected from the group consisting ofmethyl, ethyl, n-propyl, allyl and 'y-methoxypropyl and Y is selectedfrom the group consisting of hydrogen, methyl, ethyl and a residue of anon-toxic inorganic or organic base.

5. A 3-amino-2,4, 6-triiodobenzoic acid derivative according to claim 1having the formula in which R is selected from the group consisting ofmethyl, ethyl and allyl, R is selected from the group consisting ofmethyl, ethyl, n-propyl, allyl and -methoxypropyl and Y is selected fromthe group consisting of hydrogen, methyl, ethyl and a residue of anon-toxic inorganic or organic base.

6. The compound according to claim 1 the sodium salt ofN-(3-N'-acetyl-N'-methylamino-2,4,6-triiodobenzoyl)-N-allyl-,B-aminopropionic acid.

7. The compound according to claim 1 the sodium salt of N-3-N'-acetyl-N-methylamino-2,4,6-triiodobenzoyl)N-allyl-[i-amino-a-methylpropionic acid.

8. The compound according to claim 1 the sodium salt ofN-(3-N-propionyl-N'-ethylamino-2,4,6-triiodobenzoyl)-N-3-methoxypropyl-B-aminopropionicacid.

9. The compound according to claim 1 the sodium salt of N-3-N'-acetyl-N'-allylamino-2,4,6-triiodobenzoyl) -N-methyl-B-aminopropionic acid.

10. The compound according to claim 1 the sodium salt ofN-(3-N'-acetyl-N-allylamino-2,4,6-triiodobenzoyl)-N-ethyl-B-aminopropionicacid.

11. The compound according to claim 1 the sodium salt ofN-(3-N'-propionyl-N'-allylamino-2,4,6-triiodobenzoyl)43-amino-u-methylpropionicacid.

References Cited UNITED STATES PATENTS 3,334,134 8/1967 Obendorf et al.

LORRAINE A. WEINBERGER, Primary Examiner L. ARNOLD THAXTON, AssistantExaminer US. Cl. X.R.

